OncogenicMYCActivatesaFeedforwardRegulatoryLoopPromotingEssential Amino AcidMetabolismandTumorigenesis.

Most tumor cells exhibit obligatory demands foressential amino acids(EAAs), but theregulatorymechanisms whereby tumor cells take up EAAs and EAAs promote malignant transformation remain to be determined. Here, we show thatoncogenicMYC, solute carrier family (SLC) 7 member 5 (SLC7A5), and SLC43A1 constitute afeedforwardactivationloopto promote EAA transport andtumorigenesis.MYCselectivelyactivatesSlc7a5 and Slc43a1 transcription through direct binding to specific E box elements within both genes, enabling effective EAA import. Elevated EAAs, in turn, stimulateMycmRNA translation, in part through attenuation of the GCN2-eIF2α-ATF4aminoacidstress response pathway, leading toMYC-dependent transcriptional amplification. SLC7A5/SLC43A1 depletion inhibitsMYCexpression,metabolicreprogramming, and tumor cell growth in vitro and in vivo. These findings thus reveal aMYC-SLC7A5/SLC43A1 signaling circuit that underlies EAAmetabolism,MYCderegulation, andtumorigenesis.